Date of Award

4-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Bioanalysis

Research Advisor

Murali M. Yallapu Ph.D.

Committee

Subhash C. Chauhan, Ph.D; Santosh Kumar, Ph.D.; Wei Li, Ph.D.; Yi Lu, Ph.D; Liza Makowski, Ph.D.

Abstract

Resistance to conventional chemotherapy is a big challenge in the treatment of cancer including non-small cell lung cancer (NSCLC). A combination of natural chemo sensitizer agents with chemotherapy offers unique advantages over monotherapy alone. However, free unbound drugs, (in combination or as a single agent), lack tumor-targeted accumulation and therefore can be easily eliminated from the patient body. Moreover, some drugs are hydrophobic, and their organic solvents cause in vivo toxicity, thereby limiting their capability in clinical translation. Herein, dual loaded biocompatible and biodegradable nanoparticles (NPs) using Gemcitabine (Gem)a pyrimidine nucleoside antimetabolite and Gambogic acid (GA) (a highly hydrophobic chemo sensitizer agent)- were developed on human serum albumin-tannic acid nano-platform (HTA) for targeted treatment of NSCLC.Our in vitro results demonstrate that Gem and GA combination therapy has tremendous potential due to their high efficacy on NSCLC, and GA sensitize NSCLC to Gem therapy. However, GA used in combination with Gem suffers from limited solubility which subsequently leads to a decline in therapeutic efficacy. Therefore, in order to overcome this, in the present study GA and Gem were encapsulated in human serum albumin-tannic acid nanoparticles by the solvent evaporation method. In this platform, HTA is a biocompatible nanocarrier that binds to both GA and Gem. Physico chemical characterizations studies revealed that GA and Gem are successfully encapsulated in HTA NPs with uniform spherical morphology. These nanoparticles were readily taken up by NSCLC cells (A549 and H1299) in a concentration and time-dependent manner. Apart from an increase in GA solubility, encapsulated GA and Gem subsequently manifested elevated therapeutic efficacy, which was confirmed by cell viability, colony formation, migration and invasion studies. Furthermore, in vivo and ex vivo imaging analysis demonstrated notable tumor-targeting behavior of our uniquely designed HTA NPs in mice bearing A549 xenograft tumors. These findings clearly illustrate that our dual loaded NPs can be efficiently utilized to improve cancer therapy and tumor eradication.

ORCID

https://orcid.org/0000-0001-6776-4003

DOI

10.21007/etd.cghs.2019.0493

705905_supp_99BADFC6-34BC-11EA-82E0-F74259571AF4.pdf (425 kB)
Declaration of Authorship

Available for download on Tuesday, April 27, 2021

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